Alzheimer disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid a-amyloid (Aa) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Aa accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiological levels of 17a-estradiol reduce the generation of Aa by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD. Huaxi Xu et al. (1998), Nature Medicine 4, 447-451